Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease, such as arteriosclerosis. Bile acid sequestrants have been used to treat this condition; they seem to be moderately effective but they must be consumed in large quantities, i.e. several grams at a time, and they are not very palatable.
MEVACOR.RTM. (lovastatin), now commercially available is one of a group of very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase. In addition to the natural fermentation products, mevastatin and lovastatin, there are a variety of semi-synthetic and totally synthetic analogs thereof.
The preparation of the semi-synthetic and totally synthetic analogs generally involves silyl group protection of the 4-hydroxy group on these mevalonic acid derivatives. The silyl protecting group must eventually be removed, typically in the last step of the synthetic route. In prior efforts, the desilylation has been accomplished with tetra-n-butylammonium fluoride or dilute HF or methanesulfonic acid. The fluoride-based desilylation procedures were problematic on a large scale due to the corrosive properties of the reagent on pilot plant equipment. The methanesulfonic acid desilylation procedure was undesirable because it caused opening of the lactone moiety, which necessitated the introduction of a relactonization step.
The present invention introduces a novel desilylation procedure which has the advantage of increased yield over the prior procedures and increased ease of operation. The process of the present invention is not corrosive to pilot plant equipment and does not cause reactions at the lactone carbonyl.